Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents.

Kir2 subunits are believed to underlie the cardiac inwardly rectifying current I(K1). The subunit composition of native I(K1) currents is uncertain, and it has been suggested that heteromultimer formation may play a role. We studied Ba(2+) block of homo- and heteromeric Kir2 channels in Xenopus oocytes and compared the properties observed to those of human cardiac I(K1) in cells isolated from myocardial biopsies of normal human hearts. Homomeric expression of Kir2.1 and Kir2.3 produced currents with similar Ba(2+) sensitivities (e.g. IC(50) at -120 mV: 16.2+/-3.4, n=11 and 18.5+/-2.1, n=10, respectively), but these were less sensitive to Ba(2+) than native I(K1) (4.7+/-0.5 microM, n=10, P=0.001, P<0.001, respectively) and had different Ba(2+) blocking kinetics from cardiac I(K1). Kir2.2 sensitivity was similar to cardiac I(K1) (e.g., 2.8+/-0.4 microM, Kir2.2, n=9, vs. 4.7+/-0.5 microM for I(K1)), but the blocking kinetics of Kir2.2 were faster than those of I(K1). Currents resulting from co-expression of Kir2 subunits had similar Ba(2+) sensitivities and blocking kinetics among groups and were similar to I(K1) in both Ba(2+) sensitivity (e.g., IC(50) at -120 mV: 4.5+/-1.0, 2.5+/-0.5, and 2.3+/-0.4 microM for co-injected Kir2.1/2.2, n=6, Kir2.1/2.3, n=5, and Kir2.2/2.3, n=4, respectively) and blocking kinetics. Co-injection of Kir2 subunits results in currents with Ba(2+) blocking properties different from homomeric Kir2 expression but similar to cardiac I(K1). These observations suggest that a substantial proportion of native I(K1) may result from heteromultimer formation among diverse Kir2 family subunits.